Abstract: Background: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the
clinical significance and the underlying genetics of low ALP in unselected populations are unclear.
Methods: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals
(age range 20–77 yr) with unexplained low ALP levels.
Results: Nine hadmild hyperphosphatemia and three hadmild hypercalcemia. ALP levelswere inversely correlated
with serum calcium (r = -0.38, p = 0.012), pyridoxal phosphate (PLP; r = -0.51, p = 0.001) and urine
phosphoethanolamine (PEA; r = -0.49, p = 0.001). Although many subjects experienced minor complaints,
such as mild musculoskeletal pain, none hadmajor health problems.Mutations in ALPL were found in 21 subjects
(50%), including six novelmutations. All but one,were heterozygousmutations.Missensemutations were themost
common (present in 18 subjects; 86%) and themajority were predicted to have a damaging effect on protein activity.
The presence of amutated allelewas associated with tooth loss (48% versus 12%; p=0.04), slightly lower levels
of serumALP (p=0.002), higher levels of PLP (p b 0.0001) and PEA (p b 0.0001), aswell asmildly increased serum
phosphate (p=0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele.
Conclusion: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the
associated clinicalmanifestations are usuallymild, in approximately 50% of the cases, enzyme activity is lowenough
to cause substrate accumulation and may predispose to defects in calcified tissues.
